Add-back Therapy Research Articles

O-269 Long term efficacy of Linzagolix in women with endometriosis-associated pain

Abstract Study question Does once-daily linzagolix taken up to 12 months maintain pain reduction observed at 6 months in women with endometriosis? Summary answer Linzagolix alone or in combination with combined add-back therapy (ABT) for 12 months maintains improvements of endometriosis-associated pain (EAP) observed at 6 months. What is known already Linzagolix is an oral GnRH antagonist under development for EAP. In the EDELWEISS 3 study, the 200mg+ABT dose met its co-primary endpoints at 3 months by reducing dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) and secondary endpoints such as DYS, NMPP, overall pelvic pain and dyschezia as well as interference of pain with daily activities at 6 months. Linzagolix 75mg significantly reduced dysmenorrhea but not NMPP at 3 months. Both doses of linzagolix were well tolerated over 6 months of treatment. Study design, size, duration EDELWEISS 6 was the extension study of EDELWEISS 3, a placebo-controlled Phase 3 study, investigating linzagolix 75mg and 200mg+ABT for up to 6 months in women with moderate to severe EAP. Subjects who completed EDELWEISS3 were invited to enter the extension study for an additional 6-month treatment on the same linzagolix dose; placebo subjects were randomized to either active dose. After end of treatment, subjects entered a drug-free post-treatment period of 6 months. Participants/materials, setting, methods Women participating to EDELWEISS 6 received linzagolix for up to 12 months consecutively. Key efficacy assessments included dysmenorrhea and non-menstrual pelvic pain (NMPP), dyspareunia (assessed with a 4-point VRS), overall pelvic pain and dyschezia (assessed with an 11-point NRS), and interference of pain with daily activities (assessed with the EHP-30 pain domain) at Month 12. We report the results for dysmenorrhea and NMPP. Main results and the role of chance Of 484 participants in EDELWEISS 3, 353 (72.9%) entered EDELWEISS 6 and were evaluated for efficacy. Demographics were similar to EDELWEISS 3 with a mean age of 35 years, a BMI of 24kg/m2 and 99% of subjects being White. Mean (SD) monthly baseline dysmenorrhea and NMPP pain scores on the VRS were 2.28 (0.41) and 1.76 (0.45), respectively. The threshold for a meaningful pain reduction was established at Month 3, being -1.10 and -0.80 for dysmenorrhea and NMPP, respectively. At Month 3, the proportion of subjects with a reduction of dysmenorrhea of 1.10 or greater, and stable or decreased use of analgesics was 45.2% for the 75mg group and 75.4% for the 200mg+ABT group, which increased to 49.6% and 84.7%, respectively, at Month 6, the end of EDELWEISS 3. At Month 12, the end of EDELWEISS 6 treatment, the proportion of subjects was further increased to 55.9% and 91.0%, respectively. For NMPP, the proportion of subjects with a reduction of 0.80 or greater and stable or decreased use of analgesics at Month 3 was 36.5% for 75 mg and 51.7% for 200mg+ABT, increased to 54% and 61% at Month 6, and increased to 59.5% and 67.6%, respectively, until Month 12. Limitations, reasons for caution Edelweiss 6 is the extension of the previously reported double blind, placebo controlled Edelweiss 3 study. The results confirm efficacy of 200mg + ABT at 12 months. Longer term data is required to further understand efficacy of GnRH antagonists in women with endometriosis associated pain. Wider implications of the findings The linzagolix 200mg+ABT group provided substantial and sustained improvement in EAP symptoms. The 75mg which did not meet the primary endpoint in EDELWEISS 3 still demonstrated marked improvements. There exists a substantial need for different treatment regimens in women suffering from endometriosis. Trial registration number NCT04335591

Impact of demographic and clinical factors on elagolix plus add-back therapy effects on patient-reported nonbleeding symptoms in women with heavy menstrual bleeding and uterine fibroids: a post hoc analysis of data from two clinical trials

To investigate the efficacy of elagolix plus add-back therapy (estradiol [1 mg] and norethindrone acetate [0.5 mg] once daily) on patient-reported nonbleeding symptoms and menstrual bleeding associated with uterine fibroids (UFs) across different subpopulations. Post hoc analysis of two phase 3 clinical trials-Elaris UF-1 and UF-2. A total of 76 (UF-1) and 77 (UF-2) US clinical sites. Women (N = 591) with UFs and heavy menstrual bleeding. Elagolix (300 mg) twice daily with add-back therapy (the indicated dose for UF-associated heavy menstrual bleeding) vs. placebo for 6 months. "Very much improved" or "much improved" change in nonbleeding symptoms (abdominal/pelvic pain, abdominal/pelvic pressure/cramping, back pain, and abdominal bloating) and menstrual bleeding measured using a Patient Global Impression of Change scale. Improvements were assessed in subpopulations stratified using baseline characteristics (age, race [self-reported], body mass index, and International Federation of Gynecology and Obstetrics fibroid classification). Across subpopulations, differences favored elagolix plus add-back therapy (vs. placebo) for most symptoms at month 1 and all symptoms at months 3 as well as 6. In patients with characteristics commonly associated with high disease burden (age >40 years, Black/African American), those treated with elagolix plus add-back therapy reported significantly greater improvements vs. placebo at months 1-6 (P<.05) for all nonbleeding and bleeding symptoms (P≤.05). Premenopausal women with heavy menstrual bleeding and UFs receiving elagolix plus add-back therapy experienced significant improvements in nonbleeding as well as bleeding symptoms from months 1-6, regardless of baseline characteristics. NCT02654054 and NCT02691494.

Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: twelve months of an ongoing randomized phase 3 trial

Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200mg twice daily with 1mg estradiol/0.5mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. This ongoing, 48-month, phase 3 study consists of a 12-month double-blind period, with randomization 4:1:2 to elagolix 200mg twice daily with add-back therapy, elagolix 200mg twice daily monotherapy for 6months followed by elagolix with add-back therapy, or placebo. The coprimary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy vs placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% vs 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% vs 36.8%; P≤.001) at 6months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of-2.43% (lumbar spine),-1.54% (total hip), and-1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of-1.58% to-1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and12. Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was <1% and was attenuated compared with bone loss observed with elagolix monotherapy.

Linzagolix therapy versus a placebo in patients with endometriosis-associated pain: a prospective, randomized, double-blind, Phase 3 study (EDELWEISS 3).

Linzagolix therapy versus a placebo in patients with endometriosis-associated pain: a prospective, randomized, double-blind, Phase 3 study (EDELWEISS 3).

Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women.

Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5mg as the morning dose and an elagolix 300mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300mg/1mg/0.5mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.

The effect of estradiol add-back: a longitudinal MRI study in prostate cancer patients.

We investigated the effect of estradiol add-back therapy (EAT) on brain activation related to cognitive function and affect in addition to putative changes in gray and white matter volume in testosterone depleted participants with prostate cancer. We conducted a randomized controlled, double-blinded trial in which 40 patients received 0.9 mg of transdermal estradiol per day for 6 months or matched placebo. Anatomical MRI and three functional MRI (fMRI) scans were obtained for the emotion recognition task, verbal memory task, and visuospatial memory task. Activation in corresponding cognitive and affective brain networks was demonstrated for all tasks. Longitudinally, there was no difference in brain activation, reaction time, or accuracy in response to the fMRI tasks between the EAT group and placebo group at 6 months. In addition, there was no detectable change in whole-brain gray or white matter volume or in hippocampal volume between the two groups after 6 months. This study supports earlier findings that EAT does not improve verbal memory or affect and has no immediate effect on hippocampal volume in testosterone depleted patients with prostate cancer.

Oral GnRH Antagonists in Combination with Estradiol and Norethindrone Acetate for Pain Relief Associated with Endometriosis: A Review of Evidence of a Novel Class of Hormonal Agents.

Current medical treatment options for endometriosis associated pains are inadequate. Evidence on effects of nonsteroidal anti-inflammatory drugs is scarce. Around one third of patients are not responsive to oral contraceptives or progestins due to progesterone resistance. Gonadotropin-releasing hormone (GnRH) agonists can only be used for a short duration because of associated side effects. Oral GnRH antagonists, including elagolix, relugolix, and linzagolix allow oral administration, induce dose dependent reduction of estradiol levels, do not cause initial flare up of endometriosis symptoms, and allow the fast return of ovarian function and menstruation after discontinuation. Elagolix at a low dose of 150 mg once daily, or the higher dose of 200 mg twice daily, significantly increased the proportion of women achieving clinically meaningful decline of dysmenorrhea, noncyclic pelvic pain, and dyspareunia. Relugolix at an oral dose of 40 mg/day results in improvement in different forms of endometriosis related pelvic pain, with an efficacy and side effect profile similar to that of GnRH agonists. Adding 1 mg of estradiol and 0.5 mg of norethindrone to 40 mg of relugolix (relugolix combination therapy) allows extension of treatment to 24 weeks with maintained efficacy and an improved side effect profile. Linzagolix, in a dose of 75 mg/day, can be used alone to treat endometriosis associated pain. For severe pelvic pain and dyspareunia, linzagolix can be used in a high dose of 200 mg/day with hormonal add-back therapy to preserve bone health.

10173 Long-Term Therapy of Elagolix + Add-Back Therapy in Women with Endometriosis-Associated Pain for 48 Months: Update on Bone Mineral Density

10173 Long-Term Therapy of Elagolix + Add-Back Therapy in Women with Endometriosis-Associated Pain for 48 Months: Update on Bone Mineral Density

Considerations on implementation of the newest treatment for symptomatic uterine fibroids: Oral GnRH antagonists.

Novel gonadotrophin releasing hormone (GnRH) antagonist treatments have recently been developed in combination with hormonal add-back therapy, as an oral treatment option for women suffering from uterine fibroids. Registration trials assessing the GnRH antagonist combination preparations with relugolix, elagolix and linzagolix have assessed treatment efficacy for fibroid-related heavy menstrual blood loss in comparison to placebo. Marketing authorization has been granted by several agencies including those in Europe, the United Kingdom and the United States. While the registration trials report a robust effect on the reduction of heavy menstrual blood loss and improvement in quality of life scores, reticence is advised before widespread prescription. In this review, we demonstrate limitations in the trial data, namely a lack of generalizability due to the restricted study population, the lack of transparency in the distribution of disease-level characteristics limiting the predictability of treatment success in the real-world diverse population, and the absence of any comparison to current alternative treatment methods. Importantly, no clinically meaningful volume reductions were found with GnRH antagonist combination preparations, and long-term safety data, particularly concerning modest but stable bone mineral density decline, need further addressing. Symptoms related to uterine fibroids adversely affect many women's quality of life and effective medical treatments are lacking. However, despite the urgent need for conservative treatments, it is vitally important that novel drugs, like combination oral GnRH antagonists, undergo sufficiently rigorous evaluation of safety, effectiveness and cost-effectiveness in a representative population and are compared with alternative treatment methods before introduction into mainstream clinical practice.

Update on the management of endometriosis-associated pain in France

The French National College of Obstetricians and Gynecologists (CNGOF) published guidelines for managing endometriosis-associated pain in 2018. Given the development of new pharmacological therapies and a review that was published in 2021, most national and international guidelines now suggest a new therapeutic approach.In addition, a novel validated screening method based on patient questionnaires and analysis of 109-miRNA saliva signatures, which combines biomarkers and artificial intelligence, opens up new avenues for overcoming diagnostic challenges in patients with pelvic pain and for avoiding laparoscopic surgery when sonography and MRI are not conclusive.Dienogest (DNG) 2 mg has been a reimbursable healthcare expense in France since 2020, and, according to recent studies, it is at least as effective as combined hormonal contraception (CHC) and can be used as an alternative to CHC for first-line treatment of endometriosis-associated pain. Since 2018, the literature concerning the use of DNG has grown considerably, and the French guidelines should be modified accordingly.The levonorgestrel intrauterine system (LNG IUS) and other available progestins per os, including DNG, or the subcutaneous implant, can be offered as first-line therapy, gonadotropin-releasing hormone (GnRH) agonists with add-back therapy (ABT) as second-line therapy.Oral GnRH antagonists are promising new medical treatments for women with endometriosis-associated pain. They competitively bind to GnRH receptors in the anterior pituitary, preventing native GnRH from binding to GnRH receptors and from stimulating the secretion of luteinizing hormone and follicle-stimulating hormone. Consequently, estradiol and progesterone production is reduced. Oral GnRH antagonists will soon be on the market in France. Given their mode of action, their efficacy is comparable to that of GnRH agonists, with the advantage of oral administration and rapid action with no flare-up effect. Combination therapy with ABT is likely to allow long-term treatment with minimal impact on bone mass. GnRH antagonists with ABT may thus be offered as second-line treatment as an alternative to GnRH agonists with ABT.This article presents an update on the management of endometriosis-associated pain in women who do not have an immediate desire for pregnancy.

O-027 Efficacy results from a phase 3, randomized, placebo-controlled trial testing two doses of linzagolix in women with endometriosis-associated pain

Abstract Study question Does once-daily linzagolix for up to 6 months reduce the pain symptoms in women with endometriosis? Summary answer Once-daily oral use of the GnRH agonist linzagolix alone or in combination with combined hormonal add-back therapy (ABT) for 24 weeks improved endometriosis-associated pain symptoms. What is known already Linzagolix is an oral GnRH antagonist under development to treat endometriosis-associated pain (EAP). In the EDELWEISS 3 study linzagolix 200mg+ABT met its co-primary endpoints at 3 months by reducing dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) in a clinically meaningful fashion along with a stable or decreased use of analgesics. Linzagolix 75mg significantly reduced DYS but not NMPP. Secondary endpoints were DYS, NMPP, overall pelvic pain, dyschezia, and dyspareunia at 6 months assessed with a numeric and/or verbal rating scale (NRS and/or VRS), and interference of pain with daily activities assessed with the Endometriosis-Health-Profile-30 (EHP-30) pain domain. Study design, size, duration EDELWEISS 3 was a randomized, double-blind, placebo-controlled Phase 3 study, investigating efficacy and safety of linzagolix 75mg and linzagolix 200mg with ABT (1mg estradiol/0.5mg norethindrone acetate) for up to 24 weeks in women with moderate to severe EAP. To qualify, subject had to demonstrate over 2 menstrual cycles at least moderate DYS and NMPP for ≥2 days each and at least moderate overall pelvic pain for ≥5 days. Participants/materials, setting, methods Eligible women with moderate to severe EAP were equally randomized to once daily oral: placebo, linzagolix 75mg or linzagolix 200mg+ABT. Efficacy assessments included DYS, NMPP, dyspareunia (assessed with a 4-point VRS), overall pelvic pain and dyschezia (assessed with an 11-point NRS), and interference of pain with daily activities (assessed with the EHP-30 pain domain). The co-primary endpoint was a responder analysis at Month 3. We present secondary endpoints at Month 6. Main results and the role of chance Participants (n = 484) had a mean age of 35 years, a BMI of 24kg/m2 with 99% of subjects being White. At Month 6, compared to placebo significant improvements in DYS and NMPP (VRS) were observed in the 200mg+ABT group, with an estimated mean change from baseline (CfB) of -1.83 (95%CI: 1.96, 1.70; difference with placebo p &amp;lt; 0.001) and 0.92 (95%CI: 1.03, 0.82; p = 0.002), respectively. For the 75mg group, the mean CfB was 1.10 (95%CI: 1.23; 0.97; p &amp;lt; 0.001) and 0.84 (95%CI: 0.95; 0.73; p = 0.048), respectively. For overall pelvic pain (NRS), marked improvements were observed with an estimated mean CfB of 3.39 (95%CI: 3.74, 3.03; p &amp;lt; 0.001) for 200mg+ABT and 2.84 (95%CI: 3.20, 2.48; p = 0.024) for 75mg. Similarly, dyschezia (NRS) was significantly improved for both groups with a mean CfB of 1.99 (95%CI: 2.29, 1.70; p = 0.012) for 200mg+ABT and -1.98 (95%CI: 2.28, 1.69; p = 0.015) for 75mg. Both doses offered a marked, statistically significant improvement in the interference of pain with daily activities as measured on the EHP-30 Pain Dimension, with an estimated mean CfB of 35.60 (95%CI: 38.73, 32.48; p &amp;lt; 0.001) and -27.37 (95%CI: 30.50, 24.25; p = 0.001) for the 200mg+ABT and 75mg group, respectively. Both doses did not provide significant improvements in dyspareunia. Limitations, reasons for caution We report data of the EDELWEISS 3 study for up to Month 6. An extension study of this trial will provide more information on the sustained effect and potential symptom recurrence after stopping treatment. Wider implications of the findings The linzagolix 200mg+ABT group provided substantial improvement in endometriosis-associated pain symptoms. The 75mg dose was less effective but demonstrated still marked improvements. There exists an substantial need for different treatment regimens in women suffering from endometriosis. Trial registration number NCT03992846

Treatment of Adolescent Endometriosis Before, During, and After Use of Gonadotropin-Releasing Hormone Agonists: A Retrospective Cohort Study

To explore the use duration of a gonadotropin-releasing hormone agonists (GnRHa) plus add-back in adolescents with laparoscopically confirmed endometriosis and the treatment course before and after GnRHa therapy. Retrospective cohort study. We identified 51 subjects with laparoscopically confirmed endometriosis who had participated in a randomized trial of a GnRHa plus add-back as adolescents between 2008 and 2012. Electronic medical records were reviewed to obtain demographic data, clinical characteristics, and treatment outcomes after trial completion. The study was deemed IRB exempt. The average age of participants during trial enrollment was 17.9±1.7 years. Thirty-three participants had stage I endometriosis (65%). The most common treatments trialed before GnRHa therapy were combined oral contraceptives (n=47, 92%) and progestin-only pills (n=23, 45%). The average duration of GnRHa use during the trial was 9.5±3.5 months; 34 subjects (67%) completed the 1-year trial. After trial completion, 23 subjects (45%) continued to use a GnRHa with add-back therapy. The mean duration of additional GnRHa use was 31.7±28.6 months, and the longest identified duration was an additional 96 months. Twenty-four subjects switched to other hormonal treatments after trial participation, most commonly oral progestins (n=15) or combined oral contraceptives (n=6). Thirteen participants (25%) returned to a therapy that had been trialed before GnRHa use. Almost half the participants in this cohort continued to use a GnRHa with add-back for treatment of endometriosis beyond the 12-month recommended duration. Treatment varied widely after discontinuation of GnRHa, with many participants returning to previously trialed medical therapies.

Elagolix With Add-Back Therapy Improves Hemoglobin Concentration in Women With Fibroid-Associated Heavy Menstrual Bleeding Across Subgroups: Post Hoc Analysis of Elaris UF-1 and UF-2 [ID: 1368060

INTRODUCTION: Premenopausal patients with fibroid-associated heavy menstrual bleeding often experience anemia-related symptoms and reduced quality of life. Here, we report the effect of elagolix with estradiol/norethindrone acetate add-back therapy (ELA+AB) on hemoglobin (Hgb) concentration across subpopulations of patients at 6 months of treatment. METHODS: This post hoc analysis from duplicate, IRB-approved, randomized, double-blind, placebo-controlled, 6-month phase 3 Elaris UF-1/UF-2 studies (NCT02654054/NCT02691494) evaluated Hgb improvement from baseline to 6 months of therapy by change in Hgb concentration and proportion of patients who achieved greater than 1 and greater than 2 g/dL improvement by subgroups (race, age, primary International Federation of Gynecology and Obstetrics [FIGO] score, and baseline menstrual blood loss volume) in prespecified anemic subpopulations (baseline Hgb≤10.5 and 10.5 to ≤12 g/dL). RESULTS: Overall, baseline demographics and clinical characteristics were balanced between groups. Regardless of subgroup, patients with mean baseline Hgb less than 10.5 g/dL receiving ELA+AB experienced significant improvements in mean Hgb concentration at 6 months, compared with placebo (P&lt;.001; no adjustment for multiple comparisons were made). These patients had a mean Hgb concentration of 11.6 g/dL at 6 months, with a range of 11.3–12.3 g/dL depending on subgroup. At 6 months, 47% of these patients had an increase of greater than 2 g/dL with a range of 41–59% depending on subgroup. CONCLUSION: ELA+AB was effective in improving Hgb concentration across subgroups of premenopausal women with uterine fibroids and anemia (Hgb &lt;10.5 g/dL), regardless of baseline demographics or clinical characteristics, which may therefore alleviate symptoms and reduce complications of anemia.

Elagolix Improves Low Hemoglobin in Women With Uterine Fibroid-Associated Heavy Menstrual Bleeding: Post Hoc Analysis of Elaris UF-1 and UF-2 [ID: 1368055

INTRODUCTION: Women with uterine fibroids (UFs) often experience heavy menstrual bleeding (HMB) and anemia. We report improvement in hemoglobin (Hgb) levels over time with elagolix (ELA) with estradiol 1 mg/norethindrone acetate 0.5 mg once-daily add-back (AB) therapy in women with UF-associated HMB. METHODS: This post hoc analysis from duplicate, IRB-approved, randomized, double-blind, placebo (PBO)-controlled, 6-month, phase 3 Elaris UF-1 and UF-2 studies (NCT02654054 and NCT02691494) evaluated ELA 300 mg twice daily plus AB versus PBO in women with UF-associated HMB. Hgb concentration (in grams/deciliter) was assessed monthly; no adjustment for multiple comparisons were made. All patients received ELA+AB in the pivotal and extension periods. Patients with baseline Hgb&gt;10.5 g/dL but ≤12 g/dL were classified as “HgbLow” and Hgb≤10.5 g/dL as “Hgb≤10.5.” RESULTS: Baseline demographics were balanced between treatment groups. Overall, by month 1 of treatment, patients receiving ELA+AB (n=395) showed significant improvement in mean change in Hgb compared with PBO (n=196, P=.001). At month 6, 58.8% (HgbLow) and 35.7% (Hgb≤10.5) of patients reached Hgb&gt;12 g/dL with ELA+AB versus 27.7% and 7.2% with PBO, respectively. Improvements in Hgb levels were sustained through 12 months (HgbLow, 59.6%; Hgb≤10.5, 46.3%). During the extension period, 49.3% of patients in the Hgb≤10.5 group treated with ELA+AB reached Hgb&gt;12 g/dL at 9 months of treatment, with responses sustained through 12 months (ELA+AB/ELA+AB, 46.3%). 71.9% of patients in the HgbLow group reached Hgb&gt;12 g/dL by 9 months, with responses sustained through 12 months (ELA+AB/ELA+AB, 59.6%). CONCLUSION: ELA+AB results in rapid, sustained improvement in Hgb levels in women with UF-HMB, regardless of starting Hgb levels.

Elagolix Plus Add-Back Consistently Improves Uterine Fibroids-Associated Bleeding and Nonbleeding Symptoms Across Subpopulations [ID: 1368059

INTRODUCTION: Patients with heavy menstrual bleeding (HMB) associated with uterine fibroids (UFs) have significantly improved menstrual blood loss (MBL) when taking elagolix+estradiol/norethindrone acetate add-back therapy (ELA+AB) versus placebo. However, data on the effect of ELA+AB on nonbleeding symptoms are limited. METHODS: This post hoc analysis from the duplicate, IRB-approved, randomized, double-blind, placebo-controlled, 6-month, phase 3 Elaris UF-1 and UF-2 studies (NCT02654054 and NCT02691494) evaluated the Patients Global Impression of Change (PGIC). Patients rated symptom change for menstrual bleeding (MB) and nonbleeding symptoms on a 7-point scale from “very much improved” (1) to “very much worse” (7). RESULTS: By 6 months, scores for the PGIC-MB and the domains of “abdominal or pelvic pain,” “abdominal or pelvic pressure,” “abdominal or pelvic cramping,” “back pain,” and “abdominal bloating” were significantly better (P&lt;.001 for all; no adjustment for multiple comparisons were made) in the ELA+AB versus placebo groups, regardless of patient age (&lt;40 years, 40 to &lt;45 years, ≥45 years), baseline MBL (less than median [187.0 mL], greater than or equal to median), International Federation of Gynecology and Obstetrics (FIGO) classification (0–3, 4, 5–8), or baseline uterine volume (less than median [356.5 cm3], greater than or equal to median). Patients receiving ELA+AB reported PGIC domain scores that consistently exceeded “minimally improved” (≤3) and often reached or exceeded “much improved” (≤2) by 6 months. CONCLUSION: ELA+AB provides better bleeding and nonbleeding symptom improvement versus placebo for patients with HMB associated with UFs, regardless of subpopulation investigated. In all populations, PGIC-MB and domain scores consistently reached or exceeded “much improved” by 6 months with ELA+AB.

A Systematic Review of Systematic Reviews on the Use of Aromatase Inhibitors for the Treatment of Endometriosis: The Evidence to Date.

Endometriosis is a chronic gynecologic condition that affects around 6-10% of reproductive age women. This clinical entity is characterized with pelvic pain, dysmenorrhea, dyspareunia, and infertility which are the most often presenting symptoms. Aromatase P450 is the key enzyme for ovarian estrogen biosynthesis and there is evidence that endometriotic lesions express aromatase and are able to synthesize their own estrogens. Aromatase inhibitors (AIs) are potent drugs that suppress the estrogen synthesis via suppression of aromatase. We performed a systematic review of systematic reviews and narrative reviews on the use of aromatase inhibitors in the medical management of endometriosis. We searched: PubMed (1950-2022), Google Scholar (2004-2022), Cochrane Library (2010-2022) and Researchgate (2010-2022). The search included the following medical subject headings (MeSH) or keywords: "Aromatase Inhibitors" AND "Endometriosis" AND "Systematic reviews" OR "Systematic review" AND "Reviews" OR "Reviews" AND "Endometriosis". The electronic database search yielded initially 12,106 studies from the different databases. Further assessment of the studies resulted in exclusion of (n = 12,015) studies due to duplicates and irrelevance; Finally, 24 studies were selected for inclusion, 5 were Systematic reviews and 19 were Narrative reviews. The 5 systematic reviews were assessed by AMSTAR-2 criteria and were found to have low quality. Narrative reviews were assessed with SANRA criteria and were found to have high-quality aromatase inhibitors are potent drugs that can manage the endometriosis-related symptoms in cases where initial medical management has failed to show positive results. However, their use is limited by the adverse effects that are linked with menopausal symptoms. aromatase inhibitors can be administered as an alternative treatment in patients. Future studies with randomized design are required to reach safer conclusions and further investigation. These studies should define the therapeutic dose, new add-back therapy modalities. Future directions should examine the most-appropriate way of administration and the duration of therapy.

Elagolix With Add-Back Rapidly Improves Nonbleeding Symptoms in Individuals With Fibroid-Associated Heavy Menstrual Bleeding [ID: 1368052

INTRODUCTION: Elagolix+estradiol/norethindrone acetate add-back therapy (ELA+AB) significantly improves heavy menstrual bleeding (HMB) in patients with uterine fibroids (UFs). Data on the effect of ELA+AB on nonbleeding symptoms in HMB-UF patients are limited. METHODS: Elaris UF-1 and UF-2 (NCT02654054 and NCT02691494) were duplicate, IRB-approved, randomized, double-blind, placebo-controlled, 6-month phase 3 studies. This post hoc analysis evaluated the Patients Global Impression of Change (PGIC) for menstrual bleeding (MB) and nonbleeding symptoms. Patients rated symptom change on a 7-point scale from “very much improved” (1) to “very much worse” (7). RESULTS: Among responders (6-month MBL &lt;80 mL and ≥50% MBL reduction from baseline), mean (SD) PGIC-MB and PGIC-abdominal bloating were better for ELA+AB versus placebo as early as 1 month (2.1 [1.3], n=199 versus 2.8 [1.5], n=22; and 3.1 [1.2], n=201 versus 3.7 [1.0], n=21, respectively) through 6 months (1.3 [0.9], n=221 versus 2.9 [1.3], n=13; and 2.3 [1.3], n=221 versus 3.7 [0.9], n=13, respectively). Patients treated with ELA+AB had improvement in symptoms at 3 months compared to placebo and at 6 months reached scores in the domains abdominal/pelvic pain (1.8 [1.1] versus 3.2 [1.0]), abdominal/pelvic pressure (1.9 [1.2] versus 3.4 [0.9]), abdominal/pelvic cramping (1.8 [1.0] versus 2.9 [1.2]), and back pain (2.3 [1.3] versus 3.2 [1.0]). Similar results were observed for the total patient population. CONCLUSION: ELA+AB provides rapid bleeding and nonbleeding symptom improvement for patients with UF-associated HMB. Improvement for ELA+AB–treated patients was observed as early as 1 month, with nonbleeding PGIC scores consistently approaching “much and very much improved” in all domains by 6 months.

Oral Gonadotropin-Releasing Hormone Antagonists for the Treatment of Uterine Leiomyomas.

Uterine leiomyomas are common hormone-responsive neoplasms that frequently cause heavy menstrual bleeding, anemia, pelvic pressure, pain, and adverse reproductive outcomes. In this overview, the efficacy and safety of oral gonadotropin-releasing hormone (GnRH) antagonists, co-administered with menopausal replacement-level steroid hormones or used at doses to avoid complete hypothalamic suppression, are reviewed for the management of uterine leiomyomas. Oral GnRH antagonists provide rapid suppression of sex steroids and avoid the initial steroidal flare and resultant temporary worsening of symptoms typically seen with parenteral GnRH agonists. Oral GnRH antagonists are effective in reducing leiomyoma-associated heavy menstrual bleeding, with high rates of amenorrhea and improved anemia and leiomyoma-associated pain, and providing modest reduction in uterine volume when used in combination with menopausal replacement-level steroid hormones. This add-back therapy can reduce hypogonadal side effects, including hot flushes and bone mineral density loss, close to levels seen with placebo therapy. Currently, both elagolix 300 mg twice daily with once-daily estradiol (1 mg) and norethindrone (0.5 mg) and relugolix 40 mg once daily with estradiol (1 mg) and norethindrone (0.5 mg) combination therapy are approved for leiomyoma treatment by the U.S. Food and Drug Administration. Linzagolix is under investigation in the United States but approved at two does with and without steroid hormones in the European Union. The efficacy of these agents appears to be robust over a wide spectrum of clinical presentations, demonstrating that worse disease parameters at baseline do not appear to inhibit efficacy. Across clinical trials, participants largely reflected the population of individuals affected by uterine leiomyomas.

Virtual Bioequivalence Assessment of Elagolix Formulations Using Physiologically Based Pharmacokinetic Modeling.

In lieu of large bioequivalence studies and exposing healthy postmenopausal women to additional drug exposure for elagolix coadministered with hormonal add-back therapy, physiologically based pharmacokinetic (PBPK) modeling was used with in vitro dissolution data to test for virtual bioequivalence. For endometriosis, elagolix is approved at doses of 150mg once daily and 200mg twice daily as a tablet. As a combination therapy, two individual tablets, consisting of an elagolix tablet and an estradiol/norethindrone acetate 1/0.5mg (E2/NETA) tablet, were utilized in Phase 3 endometriosis trials. However, the commercial combination drug products consist of a morning capsule (containing an elagolix tablet and E2/NETA tablet as a fixed-dose combination capsule, AM capsule) and an evening capsule (consisting of an elagolix tablet, PM capsule). In vitro dissolution profiles were dissimilar for the tablet and capsule formulations; thus, in vivo bioequivalence studies or a bioequivalence waiver would have been required. To simulate virtual cross-over, bioequivalence trials, in vitro dissolution data was incorporated into a previously verified PBPK model. The updated PBPK model was externally validated using relevant bioequivalence study data. Based on results of the virtual bioequivalence simulations, the commercial drug product capsules met the bioequivalence criteria of 0.80-1.25 when compared to the reference tablets. This was a novel example where PBPK modeling was utilized along with in vitro dissolution data to demonstrate virtual bioequivalence in support of a regulatory bioequivalence waiver.

Treatment of symptomatic uterine fibroids with orally active gonadotropin-releasing hormone antagonists and add-back therapy

Treatment of symptomatic uterine fibroids with orally active gonadotropin-releasing hormone antagonists and add-back therapy